Targeting Thioredoxin Reductase 1 Alleviates Severe Acute Pancreatitis by Modulating Oxidative Stress and...

Severe acute pancreatitis (SAP) is a life-threatening inflammatory disease characterized by pancreatic injury, systemic inflammatory responses, and multiorgan dysfunction. Oxidative stress is a central driver of SAP pathogenesis; however, effective targeted therapies remain limited. Thioredoxin reductase 1 (Txnrd1), a key redox-regulating selenoenzyme, has been implicated in inflammatory and oxidative stress-related disorders. Nevertheless, its contribution to SAP-associated redox imbalance and ferroptosis-related molecular alterations remains incompletely understood. SAP was induced in mice by repeated intraperitoneal injections of L-arginine. Txnrd1 expression in pancreatic tissues was assessed using mRNA sequencing, RT-qPCR, and Western blotting. In vitro, SAP-like injury was modeled in C266 pancreatic acinar cells following L-arginine stimulation. Genetic silencing or pharmacological modulation of Txnrd1 was performed to evaluate its functional role. Cell viability, oxidative stress indices, intracellular iron homeostasis, and lipid peroxidation were measured using biochemical assays. Antioxidant signaling pathways and ferroptosis-related molecular markers were analyzed by RT-qPCR, Western blotting, and immunohistochemistry. Mitochondrial ultrastructure was examined by transmission electron microscopy. In vivo oxidative stress, inflammatory responses, apoptosis, and ferroptosis-associated signaling were systematically evaluated. Txnrd1 expression was significantly upregulated in pancreatic tissues from SAP mice and in L-arginine-treated C266 cells. Genetic or pharmacological inhibition of Txnrd1 alleviated pancreatic injury and improved cellular viability. Txnrd1 suppression attenuated oxidative stress, as indicated by reduced ROS, MDA, lipid peroxidation, and intracellular ferrous iron levels, accompanied by restoration of GSH content. Antioxidant defense mechanisms were enhanced, with increased expression of Nrf2, SOD1, and HO-1. Inflammatory cytokine production, including IL-1β, IL-6, and TNF-α, was markedly reduced. Furthermore, Txnrd1 inhibition preserved mitochondrial morphology and was associated with modulation of ferroptosis-related proteins, including increased GPX4 and SLC7A11 expression and decreased levels of COX2, ACSL4, and NOX1. These findings suggest that Txnrd1 contributes to SAP progression by exacerbating oxidative stress, inflammatory responses, and ferroptosis-associated molecular signaling. Targeting Txnrd1 may therefore represent a potential therapeutic strategy for severe acute pancreatitis.